Commentary – Do the negative results of the PENUT trial close the book on erythropoietin for premature infant brain?

Volpe, Joseph J.

doi:10.3233/npm-200444

Cited by 10 publications

(9 citation statements)

References 27 publications

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“…Erythropoietin is a safe, already approved drug to treat other complications of the PTI. Altogether, our data support further assessment of EPO (Volpe, 2020) as a feasible treatment to protect against central complications associated to GM-IVH in the short (P14) and the long term (P70). Moreover we provide evidence of gelsolin, as a feasible marker for a devastating disease.…”

Section: Resultssupporting

confidence: 73%

“…The PENUT study is an extremely relevant study on the field, however, individual groups were not analyzed and it remains possible that cognitive and physical problems might become evident later in life ( Juul et al, 2020 ). Following this idea, Volpe (2020) has commented this aspect as a main limitation, also acknowledged in the study, since cognitive testing at 2 years of age is not as reliable as testing at later ages. In this sense, other studies comparing early assessments (before 3 years of age) with later cognitive tests at school age, showed a relatively low pooled sensitivity (55%) of early assessments to identify school-age cognitive deficits.…”

Section: Discussionmentioning

confidence: 98%

“…White matter development is an active process that continues well after infancy and it's closely related to specific cognitive functions that may be affected at later stages. Therefore Volpe suggests the necessity of testing longer duration of treatment, reaching full-term equivalent age or even longer (Volpe, 2020). A previous meta-analysis has also showed that that prophylactic EPO improves cognitive development (Fischer et al, 2017) and early EPO treatment may decrease the rates of necrotizing enterocolitis as well as brain complications, including IVH and periventricular leukomalacia (Ohlsson and Aher, 2017).…”

Section: Discussionmentioning

confidence: 99%

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Erythropoietin Improves Atrophy, Bleeding and Cognition in the Newborn Intraventricular Hemorrhage

Hierro-Bujalance

Infante-Garcia

Sanchez-Sotano

et al. 2020

Front. Cell Dev. Biol.

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The germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most devastating complications of prematurity. The short-and long-term neurodevelopmental consequences after severe GM-IVH are a major concern for neonatologists. These kids are at high risk of psychomotor alterations and cerebral palsy; however, therapeutic approaches are limited. Erythropoietin (EPO) has been previously used to treat several central nervous system complications due to its role in angiogenesis, neurogenesis and as growth factor. In addition, EPO is regularly used to reduce the number of transfusions in the preterm infant. Moreover, EPO crosses the blood-brain barrier and EPO receptors are expressed in the human brain throughout development. To analyze the role of EPO in the GM-IVH, we have administered intraventricular collagenase (Col) to P7 mice, as a model of GM-IVH of the preterm infant. After EPO treatment, we have characterized our animals in the short (14 days) and the long (70 days) term. In our hands, EPO treatment significantly limited brain atrophy and ventricle enlargement. EPO also restored neuronal density and ameliorated dendritic spine loss. Likewise, inflammation and small vessel bleeding were also reduced, resulting in the preservation of learning and memory abilities. Moreover, plasma gelsolin levels, as a feasible peripheral marker of GM-IVHinduced damage, recovered after EPO treatment. Altogether, our data support the positive effect of EPO treatment in our preclinical model of GM-IVH, both in the short and the long term.

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Section: Resultssupporting

confidence: 73%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Erythropoietin Improves Atrophy, Bleeding and Cognition in the Newborn Intraventricular Hemorrhage

Hierro-Bujalance

Infante-Garcia

Sanchez-Sotano

et al. 2020

Front. Cell Dev. Biol.

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“…Even though there was nothing abnormal in the imaging examination after the absorption of the hematoma, these patients probably experienced some neurological or psychological complications [ 63 ]. Such complications might not appear until school age or even later [ 64 , 65 ], so longer follow-up to allow comprehensive assessments of neurodevelopment would be valuable [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin Improves Poor Outcomes in Preterm Infants with Intraventricular Hemorrhage

Shi

Wang

et al. 2021

CNS Drugs

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Background Intraventricular hemorrhage (IVH) is a common complication in preterm infants that has poor outcomes, especially in severe cases, and there are currently no widely accepted effective treatments. Erythropoietin has been shown to be neuroprotective in neonatal brain injury. Objective The objective of this study was to evaluate the protective effect of repeated low-dose recombinant human erythropoietin (rhEPO) in preterm infants with IVH. Methods This was a single-blinded prospective randomized controlled trial. Preterm infants ≤ 32 weeks gestational age who were diagnosed with IVH within 72 h after birth were randomized to receive rhEPO 500 IU/kg or placebo (equivalent volume of saline) every other day for 2 weeks. The primary outcome was death or neurological disability assessed at 18 months of corrected age. Results A total of 316 eligible infants were included in the study, with 157 in the rhEPO group and 159 in the placebo group. Although no significant differences in mortality ( p = 0.176) or incidence of neurological disability ( p = 0.055) separately at 18 months of corrected age were seen between the rhEPO and placebo groups, significantly fewer infants had poor outcomes (death and neurological disability) in the rhEPO group: 14.9 vs. 26.4%; odds ratio (OR) 0.398; 95% confidence interval (CI) 0.199–0.796; p = 0.009. In addition, the incidence of Mental Development Index scores of < 70 was lower in the rhEPO group than in the placebo group: 7.2 vs. 15.3%; OR 0.326; 95% CI 0.122–0.875; p = 0.026. Conclusions Treatment with repeated low-dose rhEPO improved outcomes in preterm infants with IVH. Trial Registration The study was retrospectively registered on ClinicalTrials.gov on 16 April 2019 (NCT03914690).

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“…55 Brain magnetic resonance imaging (MRI) plus tractography at term equivalent age showed less white matter injury and improved connectivity in the Epo-treated group in comparison with the placebo group. 58 Despite these promising imaging findings, neurodevelopmental outcome at 2 years of age did not differ significantly between groups. 59 An argument against these finding could be that the assessment of more complex cognitive functions, such as executive functions, is only possible at a later age.…”

Section: Erythropoietinmentioning

confidence: 90%

Pharmacological Neuroprotection of the Preterm Brain: Current Evidence and Perspectives

Siahanidou

Spiliopoulou

2020

Am J Perinatol

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Despite improvements in viability, the long-term neurodevelopmental outcomes of preterm babies remain serious concern as a significant percentage of these infants develop neurological and/or intellectual impairment, and they are also at increased risk of psychiatric illnesses later in life. The current challenge is to develop neuroprotective approaches to improve adverse outcomes in preterm survivors. The purpose of this review was to provide an overview of the current evidence on pharmacological agents targeting the neuroprotection of the preterm brain. Among them, magnesium sulfate, given antenatally to pregnant women with imminent preterm birth before 30 to 34 weeks of gestation, as well as caffeine administered to preterm infants after birth, exhibited neuroprotective effects for human preterm brain. Erythropoietin treatment of preterm infants did not result in neuroprotection at 2 years of age in two out of three published large randomized controlled trials; however, long-term follow-up of these infants is needed to come to definite conclusions. Further studies are also required to assess whether melatonin, neurosteroids, inhaled nitric oxide, allopurinol, or dietary supplements (omega-3 fatty acids, choline, curcumin, etc.) could be implemented as neuroprotectants in clinical practice. Furthermore, other pharmacological agents showing promising signs of neuroprotective efficacy in preclinical studies (growth factors, hyaluronidase inhibitors or treatment, antidiabetic drugs, cannabidiol, histamine-H3 receptor antagonists, etc.), as well as stem cell- or exosomal-based therapies and nanomedicine, may prove useful in the future as potential neuroprotective approaches for human preterm brain. Key Points

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Commentary – Do the negative results of the PENUT trial close the book on erythropoietin for premature infant brain?

Cited by 10 publications

References 27 publications

Erythropoietin Improves Atrophy, Bleeding and Cognition in the Newborn Intraventricular Hemorrhage

Erythropoietin Improves Atrophy, Bleeding and Cognition in the Newborn Intraventricular Hemorrhage

Erythropoietin Improves Poor Outcomes in Preterm Infants with Intraventricular Hemorrhage

Pharmacological Neuroprotection of the Preterm Brain: Current Evidence and Perspectives

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